6-(m-AMINO AND SUBSTITUTED-AMINO PHENYL)-2,3,5,6-TETRAHYDRO{8 2,1-b{9 THIAZOLES AND METHOD OF USE

ABSTRACT

d1 and 1 compounds of the formula:   AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF. The invention also relates to a novel method for the preparation of these compounds and to the use of said compounds for treating helminthiasis in warm-blooded animals.

Unite States mm Spicer et al.

[ June 27, 1972 Larry Dean Splcer, Princeton; John James Hand, Trenton, both of NJ.

inventors:

Assignee: American Cyanamid Company, Stamford,

Conn.

Filed: March 25, 1970 Appl. No.: 22,701

US. Cl ..260/306.7, 424/270 Int. Cl. ..C07d 91/18 Field of Search ..260/306.7

References Cited UNITED STATES PATENTS 12/1970 Bullock ..260/564 3,274,209 9/1966 Raeymakersetal ..260/306.7

Primary Examiner-Alex Mazel Assistant ExaminerR. V. Rush Attorney-Ernest Y. Miller [57] ABSTRACT di and 1 compounds of the formula:

and the pharmaceutically acceptable salts thereof. The invention also relates to a novel method for the preparation of these compounds and to the use of said compounds for treating helminthiasis in warm-blooded animals.

4 Claims, No Drawings 6-(M-AMIN0 AND SUBSTITUTED-AMINO PHENYL)- 2,3 ,5 ,6-TETRAHYDRO[2,1-B]THIAZOLES AND METHOD OF USE BACKGROUND OF THE INVENTION A number of 6-substituted-imidazo[2,1-b]thiazoles are generically disclosed by Raeymakers et al. in their US. Pats. No. 3,274,209, issued Sept. 20, 1966 and US. Pat. No. 3,364,112, issued Jan. 16, 1968. Use of these compounds as anthelmintic agents is also suggested and data for several compounds are described. The compounds actually exemplified, however, have their limitations. This is especially evident when such compounds are employed for control of whipworms, particularly in Canidae. While both the optically inactive dl 6-phenyl-2,3,5,6-tetrahydroimidazo[2,l-b]thiazole of Raeymakers et al. and the optically active 1(-)6-phenyl- 2,3,5,6-tetrahydroimidazo[2,l-b]thiazole of Bullock, US. Pat No. 3,463,786, issued Aug. 26, 1969 are highly effective against most helminths, they are not sufficiently active against whipworms, especially in dogs, to permit the use of a dosage level which will effectively control whipworm infestations while maintaining a margin of safety considered to be desirable or acceptable.

DESCRIPTION OF THE lNVENTlON Surprisingly, we have now found that effective and safe whipworm control in warm-blooded animals can be obtained with a very select group ofdl and l compounds of the formula:

Y 1.... i l

and phannaceutically acceptable acid addition salts thereof. These salts can be the hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like.

In accordance with the present invention, an appropriate anilide such as 3-acetylacetanilide, 3-acetylformanilide, 3'- acetylpropionanilide is dissolved in an inert solvent such as methylene chloride, chloroform, carbon tetrachloride or the like, and treated with bromine, chlorine, or the like, to form the corresponding 3-chloro or 3'-bromoacetylacetanilide, formanilide or propionanilide shown as formula (I) on the flow diagram hereinafter.

T of the formula (1) anilide with an equimolor amount of 2- aminothiazole or 2-amino-2-thiazoline in an solvent such as methylene chloride, chloroform, acetone, ethyl acetate or the like, at a temperature between about C. and 75 C., yields the 3 2-imino-4-thiazolin-3-yl )acetyl acetanilide, formanilide, or propionanilide, hydrochloride or hydrobromide salt of formula (ll). This salt is treated with at least the theoretical amount of an alkali metal borohydride in the presence of a lower alcohol such as methanol, ethanol, butanol, isopropanol, water-lower alcohol or the like and then acidified with an organic or hydrohalide mineral acid to form the hydroxyethyl acetanilide hydrohalide or formula (IVB). We have also found the formula (II) imino-thiazolinyl anilide hydrohalide can be treated with acetic anhydride in the presence of an inert solvent such as acetic acid and an alkali metal acetate at a temperature between about 50 and 120 C. to obtain the formula (III) 2-acetylimino thiazolinyl anilide NHCORs NCOCHs which is readily converted to the thiazolinyl anilide hydrohalide of formula (IVA) by reaction with an alkali metal borohydride followed by acidification. The reaction conditions used are similar to the alkali metal borohydride treatment of the formula (11) compounds.

Cyclization of the thiazolinyl anilide hydrohalide (formula IV) by reacting said compound with thionyl chloride at a temperature between about 40 and C. and treating the reaction product with acetic anhydride at about 50 to 140 C. The reaction product is then dissolved in hydrochloric acid and made basic with ammonium hydroxide or an alkali metal hydroxide to yield the dihydroimidazo thiazolyl acetanilide shown as formula (V). If this product is then treated with perchloric acid, the perchlorate salt of formula (V) is obtained.

Cyclization of the formula (IV) compounds can also be achieved by reaction with concentrated sulfuric acid followed by treatment of the reaction product with strong base such as formula (V) with hydrochloric or hydrobromic acid at refluxing temperature yields the aminophenyl imidazo thiazole dihydrohalide of formula (Vll).

Advantageously, the formula (VII) compound can also be prepared from 2,3,5,6-tetrahydro-6-(m-nitrophenyl)imidazo[ 2,l-b]-thiazole hydrochloride (V1) by reacting such compound with stannous chloride and hydrochloric acid at higher temperature, for example, between about 60 and C. The resulting product is then neutralized with an alkali metal hydroxide and the mixture treated with an alcohol hydrohalide.

Also, in accordance with the present invention, l-6-(maminophenyl )-2,3 ,5 ,6-tetrahydroimidazo[ 2, l -b]thiazole dihydrochloride is obtained by resolution of racemic dl2,3 ,5 ,6-tetrahydro-6-(m-nitrophenyl )imidazo[ 2, l b]thiazole with d-tartaric acid to give the l-base, d-tartarate salt which is converted to the free base and then to the lisomer, l-6-(m-nitrophenyl )-2,3 ,5 ,6-tetrahydroimidazo[2,1- b]thiazole hydrochloride. Reduction of l-6-(m-nitrophenyl)- 2,3 ,5 ,6-tetrahydroimidazo 2, l-b ]-thiazole hydrochloride with stannous chloride in hydrochloric acid gives the desired [-6- (m-aminophenyl )-2,3 ,5 ,6-tetrahydroimidazo[2,1-b]thiazole dihu xedzls This sast aizisillvsta tsas $9 325 zole hydrochloride.

NH: l-ti-(m-aminophenyl)-2,3,5,fi-tetruhydroimidazo-l2.l;b]thiazole dilly: chlofi'de and Q-(S-m-aminophenyl)2,3,5,fitetrahydromidazoBJQ]thiazole dillydrochloride.

snclz VII The reactions described above can be illustrated by the following:

Flow diagram 1 C12 01 BM S #30011. -c0cHix w ung NHCORQ IA Ra= CH3 X=Br S NHCORQ NHCO R3 IIIA R3= CH3 mso. H

NHCOR3 VA R 0 H X =perchl0rlc acid (l-isdmer) VIIA X= Cl VIIB X=c1 VIIC X=Cl I-lsomer wherein R is hydrogen or acetyl, R is hydrogen or lower alkyl (C,-C and X is an anion as shown.

The compounds of the present invention are useful as anthelmintic agents effective for treating helminthiasis in warm-blooded animals.

They are highly effective at very low dosage levels, for example, at from 1 to about mg./kg. of body weight and preferably are utilized at dose levels from 1.5 to 5.0 mg./kg. of body weight of warm-blooded animal. importantly, they are effective for removing all of the important gastrointestinal nematodes, namely, ascarids, hookworms, whipworms and tapeworms. They have the advantage over their known relatives of being highly effective against whipworms, a helminth heretofore extremely difficult to control. They may be used for treatment of helminthiasis in laboratory, farm and domestic animals as well as wild animals held in captivity and are particularly useful in the treatment of helminthiasis in Canidae.

Advantageously, the active compounds may be administered orally or parenterally. They may be administered orally in the form of a tablet, pill, capsule, bolus, drench, liquid formulation or in the feed. When used parenterally, the compound is generally dissolved in a pharmaceutically acceptable carrier such as distilled water, polyethyleneglycol or the like and adjusted to a pH between 3.5 to 6.5 and given by subcutaneous or intramuscular injection.

DETAILED DESCRIPTION The following examples describe in detail the preparation of compounds of this invention and the testing of representative compounds against helminths in warm-blooded animals.

EXANIPLE 1 Preparation of 3'-Bromoacetylacetanilide (1A) To a stirred solution of 110.0 g. (0.62 mole) of 3'- acetylacetanilide in 2,400 m1. of chloroform is added dropwise a solution of 33.0 ml. 102.9 g; 0.644 mole) of bromine in 240 ml. of chloroform. The solution is stirred one hour and the resultant precipitate is then filtered, washed with ether and dried. The solid is stirred in a large volume of water to give an oily precipitate which crystallizes on further stirring. The solid is filtered, washed with water and then 2-propanol. The dried product weighs 148.34 g., and is recrystallized from 2- propanol to give the product, melting point 108.5l 10 C. Analysis: Calcd. for C l-l BrNo z Calcd: C, 46.90; H, 3.94; Br, 31.20; N, 5.47. Found: C, 47.12; H, 3.94; Br, 31.21; N, 5.47.

EXAMPLE 2 Preparation of 3 -[(2-Imino-4-thiazolin-3- yl )acetyl ]acetanilide hydrobromide (MA) A solution of 64.8 g. (0.253 mole) of 3'-bromoacetyl acetanilide (Example 1) and 25.3 g. (0.253 mole) of 2- aminothiazole in 450 ml. of acetone is heated at 5060 C. for two hours. The precipitated product is filtered, washed with acetone and dried to give 58.74 g., of crude product which on recrystallization from methanol-ether gives the product melting point 225 dec. Anal. Calcd. for C, -,H,.,BrH O S: C, 43.83; H, 3.96; Br, 22.43; N, 11.80; S, 9.00. Found: C, 43.90; H, 4.21; Br, 22.21; N, 11.73; S, 8.69.

EXAMPLE3 Preparation of 3 2-lrnino-3-thiazolidinyl)acetyl]acetanilide hydrobromide (IIB) A solution of 5.12 g. 0.020 mole) of 3'- bromoacetylacetanilide in ml. of acetone is added to a stirred solution of 2.04 g. (0.020 mole) of 2-amino-2- thiazoline in 30 ml. of acetone. The mixture is stirred 1.5 hour and the precipitate then filtered, washed with acetone and dried to give 6.00 g. of white solid, which on recrystallization from water gives the product, melting point 275277 C.

Anal. Calcd. for C l-1 BrN O S: C, 43.58; H, 4.50; Br, 22.31; N, 11.73; S, 8.95. Found: C, 43.99; H, 4.66; Br, 22.51; N, 11.72; S, 9.14.

EXAMPLE 4 Preparation of 3 '-[2-(acetylimino) -4-thiazolin-3-yl]acetyl acetanilidine (111A) A mixture of 35.6 g. (0.10 mole) of 3'-[2-imino-4-thiazolin- 3-yl)acetyl]acetani1ide hydrobromide (Example 2) l 1.8 g. (0.12 mole) of potassium acetate, ml. of acetic anhydride and 150 ml. of acetic acid is stirred at reflux for 1 hour. The mixture is cooled to 50 C., filtered, and the filtrate evaporated at reduced pressure. The residue is azeotroped with toluene, then triturated with 2-propanol and filtered to give 25.8 g. of crude product, which on recrystallization from aqueous acetic acid gives the product, melting point 224226 C.

Anal. Calcd. for C l-l N O S: C, 56.77; H, 4.76; N, 13.24; S, 10.10. Found: C, 56.88; H,4.'77; N, 13.16; S, 9.90.

EXAMPLE 5 Preparation of 3-2-[2-(acetylirnino)-4-thiazolin-3-yl]- lhydroxy-ethylacetanilide hydrobromide (IVA) To a stirred mixture of 3.2 g. (0.01 mole) of 3'-[2- (acetylirnino)-4-thiazo1in-3-yl]acetyl acetanilide (Example 4) in 30 ml. of 95 percent ethanol is added 0.30 g. (0.0078 mole) of sodium borohydride. The mixture is stirred 2.5 hours, poured into water and acidified with acetic acid. The solution is evaporated under reduced pressure and the residue crystallized from dilute hydrobromic acid to give 2.25 g. of product, which on recrystallization from water gives the product, melting point 228 C., dec. Anal. Calcd. for C H BrN O S: C, 45,00; 1!, 4.53; Br, 19.96; N, 10.50; S, 8.01. Found: C, 45.11; H, 4.81; H, 4.81; Br, 20.16; N, 10.57; S, 7.74.

EXAMPLE 6 Preparation of 3'-[ l-Hydroxy-2-(2-imino-3- thiazolidinyl)ethyl]-acetanilide hydrochloride (IVB) To a stirred slurry of 63.47 g. (0.177 mole) of 3'-[(2-imino- 3-thiazolidinyl)acetyl]acetanilide hydrobromide (Example 3) in 1 liter of 95 percent ethanol, maintained at 5 C., is added 5.70 g. (0.1 mole) of sodium borohydride. After stirring 40 minutes au'vidditional 4.10 g. of sodium borohydride is added and the ixture is acidified with hydrochloric acid and evaporated under reduced pressure. The residue is portioned between chloroform and dilute aqueous ammonium hydroxide. Two further chloroform extracts are combined with the original, washed with brine, dried (sodium sulfate) and evaporated to give an oil. Treatment with acetone gives 26.77 g. (48 percent) of white crystalline hydrochloride, which has melting point 235-237 C. Analysis: Calcd. for C I-l ClN S: Calcd: C, 49.44; H, 5.74; C1, 11.23; N, 13.31; S, 10.15. Found: C, 49.87; H, 5.27;Cl, 11.51; N, 13.25; S, 10.40.

EXAMPLE 7 Preparation of 3'-[5,6-Dihydroimidazo[2,1-b]thiazol-6- yl)acetylanilide perchlorate (VA) To a stirred mixture of 6.00 g. (0.015 mole) of 3 2-[2- (acetylimino )-4-thiazolin-3-yl 1 -hydroxyethy1 acetanilide hydrobromide (Example in 90 ml. of dry DMF (dimethylformamide) is added dropwise, 2.0 g. (0.017 mole) of thionyl chloride. The mixture is stirred two hours at 50-55 C. then cooled to 25 C. and stirred while 1.17 g. (0.0099 mole) of thionyl chloride is added dropwise. The mixture is stirred 30 minutes at 25 c. and then at 5055 C. for one hour. .The mixture is cooled, filtered, and the filtrate evaporated at reduced pressure. After refluxing the residue in 100 ml. of acetic anhydride for 1.5 hours, the acetic anhydride is distilled at reduced pressure. The residue is dissolved in dilute hydrochloric acid, filtered, made basic with conc. arrunonium hydroxide and extracted twice with methylene chloride. The combined organic layers are extracted with dilute hydrochloric acid and the product extracted with base back into methylene chloride. The dried methylene chloride solution is evaporated to give an oil which is converted to the perchlorate salt, which on recrystallization from 95 percent ethanol gives the product, melting point l85-l87 C. Analysis: Calcd. for C H CIN O S: Calcd: C, 43.39; H, 3.92; Cl, 9.85; N, 11.68; S, 8.91. Found: C, 43.37; H, 3.82; Cl, 9.90; N, 11.50; S, 8.82.

EXAMPLE 8 Preparation of 3-(2,3,5,6-Tetrahydroirnidazo[2,1-b]thiazol- 6-yl)-acetanilide (VB) Addition of 5.00 g. (0.0158 mole) of 3'-[1-hydroxy-2-(2- imino-3-thiazolidinyl)ethyl]acetanilide hydrochloride (Example 6) to 15 ml. of concentrated sulfuric acid is carried out in small increments over 0.5 hour. The orange solution is stirred an additional 1 hour, poured onto ice and made basic with concentrated ammonium hydroxide. The aqueous base is extracted twice with chloroform and the combined organic layers washed with water, brine, dried (sodium sulfate) and evaporated at reduced pressure to give 3.76 g. of an oil. Crystallization from ether gives 3.32 g. percent crude yield) of fine white crystals, which on recrystallization from 2- propanol gives the produce. melting point l64166 C. Analysis: Calcd. for C H N OS: Calcd: C, 59.74; H, 5.79; N, 16.08; 8, 12.27. Found: C, 59.93;]1, 5.85;N, 15.96; S, 12.49.

EXAMPLE 9 Preparation of 6-(m-Aminophenyl)-5,6-dihydroimidazo[ 2, 1 b]thiazole dihydrochloride VIlA) A 2.80 g. (0.0078 mole) portion of 3'-(5,6-dihydroimidazo[2,l-b]thiazol-6-yl)acetanilide perchlorate (Example 7) is converted to the free base and then dissolved in 15 ml. of 6N hydrochloric acid. The solution is stirred at reflux for 1.6 hours and then evaporated at reduced pressure. The residue is azeotroped with 2-propanol and crystallized from percent ethano1/2-propano1 to give 1.69 g. (75 percent of crystalline product, melting point 242-244 C. Anal. Calcd. for C H CI N S: C, 45.54; H, 4.52; Cl, 24.42; N, 14.48; S, 11.05. Found: C, 45.39; H, 4.66; C1, 24.26; N, 12.27; S, 10.83.

EXAMPLE 10 Preparation of 6-(mAminophenyl)-2,3,5 ,6- tetrahydroimidazo[2, 1 -b]-thiazole Dihydrochloride (VllB) A solution of 1.00 g. (0.0038 mole) of 3'-(2,3,5,6- tetrahydroimidazo[2,1-b]thiazo1-6-yl)acetanilide (Example 8) in 17 ml. of 6N hydrochloric acid is heated at reflux for 2.5 hours and then allowed to stand overnight at room temperature. The solution is concentrated at reduced pressure, made basic with concentrated aqueous sodium hydroxide while cooling and then extracted with 3 portions of chloroform. The combined organic layers are washed with brine, dried (sodium sulfate) and evaporated to give 0.84 g. of an oil, i.e., maminotetramisole free base. The oil is dissolved in hot methanol and strongly acidified with hydrogen chloride in 2- propanol. Evaporation of the solution and crystallization of the residue from 2 -propanol gives 0.91 g. (81 percent) of cream colored solid, melting point l98201 C., dec.

EXAMPLE 11 Preparation of 6-( m-Aminophenyl)-2,3,5,6- 'tetrahydroimidazo 2, 1-b]-thiazole Dihydrochloride (VIIB) To a stirred slurry of 22.57 g. (0.01 mole) of stannous chloride dihydrate in 35 ml. of cone. hydrochloric acid, cooled to 5 C. is added 7.14 g. (0.025 mole) of 6-(mnitrophenyl)-2,3,5,6-tetrahydroimidazo[thiazole hydrochloride in one portion. The reaction is allowed to proceed at 40 C. for 30 minutes and then heated at 7580 C. for 3 hours. After pouring onto ice, the mixture is neutralized with aqueous sodium hydroxide and extracted into methylene chloride. The methylene chloride solution is washed with water, dried (magnesium sulfate) and evaporated at reduced pressure to give the free base as a yellow oil. The free base is dissolved in methanol and treated with excess 2- propanol-hydrogen chloride. Evaporation of the solvent and treatment of the oil residue with acetonitrile gives 5.08 g. (68 percent yield) of crude product which is recrystallized from 95 percent ethanol to give the white product, melting point 202 205 C. Anal. Calcd. for C H N SCI C, 45.21; H, 5.17; N, 14.38; S, 10.97; Cl, 24.27.

EXAMPLE 12 Preparation of 1-2,3,5 ,6Tetrahydro-6-( mnitrophenyl )imidazo- 2, 1 -b]thiazole Hydrochloride (VIA) Procedure A A 28.58 g. (0.10 mole) portion of the dl-6-(m-nitrophenyl)- 2,3 ,5 ,6-tetrahydroimidazo[2,1-b]thiazole hydrochloride (Example 1 1) is converted to the free base. A mixture of the free base, 15.0 1 g. (0.10 mole) of d-tartaric acid and 520 ml. of 95 percent ethanol is heated on the steam bath and then allowed to cool to 30C. The precipitated salt is filtered, washed with ethanol and dried to give 15.4 g. (77 percent) of the l-base, dacid salt, melting point 181l82 C., dec., [ah-58. 1 (C 7.7, H Two recrystallizations from 90 percent ethanol give the analytical sample, melting point 182 C., dec. [04],, 603 (c 7.5, H 0).

EXAMPLE l3 Isolation of 1-6-(m-Nitrophenyl)-2,3,5,6- tetrahydroimidazo[2, l e-b]-thiazole hydrochloride (VIB) Conversion of 10.4 g. of l-base, d-tartrate salt to the free base and treatment of an ethanolic solution of the free base with 2-propanol-hydrogen chloride gives 7.05 g. of l-6-(mnitrophenyl )-2,3 ,5 ,6-tetrahydroimidazo[ 2, l -b]thiazole hydrochloride, melting point 209-2l0 C., [ah -96.9 (c 6.7, H 0). Two recrystallizations from ethanol gives the essentially pure product with [a],,99.4 (c 6.4, H 0).

EXAMPLE 14 Preparation of 1-6-(m-Aminophenyl)-2,3,5,6- tetrahydroimidazo-[2,1-b]thiazole Dihydrochloride (VIlC) The procedure described for the reduction of 6-(mnitrophenyl)-2,3,5,6-tetrahydroimidazo[2, l -b]thiazole hydrochloride is followed. From 14.98 g. (0.0524 mole) of l- 2,3,5,6-tetrahydro-6-(m-nitrophenyl)imidazo[2,l-blthiazole hydrochloride (Example 12) is obtained 11.03 g. of the product free base as an oil. The free base is dissolved in methanol and acidified with 2-propanol-hydrogen chloride to give 9.97 g. (68 percent yield) of white crystalline product, melting point 273276 C., [01],, 78.5 (c 10, P1 0). The analytical sample, melting point 276.5279 C., is obtained from water/2-propanol. Anal. Calcd. for c,,1-i,,N,sc1,= C, 45.21; H, 5.17; N, 14.38; S, 10.97; Cl, 24.27. Found: C, 45.23; H, 5.19; N, 14.34; S, 11.08;C1, 24.17.

EXAMPLE 15 Preparation of d-2,3 ,5 ,6-Tetrahydro-6-(maminophenyl )imidazo-[2, l -b]thiazo1e Dihydrochloride (VIID) The procedure described in Example 16 is followed. From 14.00 g. (0.0491 mole) of d-6-(m-nitrophenyl)-2,3,5,6- tetrahydroimidazo[2,1-b]thiazole hydrochloride (obtained from d, l-6 (m-nitrophenyl-2,3,5,6-tetrahydroimidazo[2,1- b]thiazo1e hydrochloride and l-tartaric acid) is obtained 12.75 g. (89 percent) recrystallized d-6-(m-aminophenyl)-2,3,5,6- tetrahydroimidazo[2,1-b]thiazole dihydrochloride, melting point 277278 C., [o:],, 84.6 (c 9.9, 11 0). Anal. Found: C, 45.39; H,5.21;N, 14.47; S, 11.19;

EXAMPLE 16 Albino female mice are each inoculated with about 20 infectious larvae of Nematospiroides dubius. This nematode is a representative of the economically important trichostrongylid worms of ruminants and other hosts, and of nematodes in general. Twenty-two days after inoculation, groups'of four randomly selected mice containing adult N. dubius are given single oral doses or test compounds dissolved or suspended in 0.4 ml. of water per 20 gram mouse. At 26 or 27 days after inoculation, treated mice and in each test four randomly selected groups of untreated mice are necropsied. The number of worms in the small intestine of each mouse are determined by microscopic examination. Average worm numbers for each treated group and for the untreated controls are computed and the percent efficacy determined by the customary formula:

Average Worms in Control-Average Worms irrTrc-atcd Average Worms in Control 7 X 9 Using the above procedure, (Table I) hereinafter gives results from representative tests with dl-m-amino tetramisole, 6-(maminophenyl )-2,3,5,6-tetrahydro, imidazo[ 2, 1 -b ]thiazole dihydrochloride. Each result in (Table 1) represents one group of treated mice. The total results show that the approximate dose which removes 50 percent of the worms, the ED 1.0 mg./kg. This indicates unusually high activity for a tetramisole type compound.

TABLE 1 Efficacy of dl m-amino Tetramisole Versus N. dubius by Single Oral Dose Dose Av.% MgJKg. Efficacy per Group Efficacy EXAMPLE 1? Data obtained by the above procedures (Example 16) for the unsubstituted dl-tetramisole in mice against N. dubius show an ED of about 9 mg./kg. (TA Table 2 hereinafter). Accordingly, m-amino tetramisole is approximately nine times as active as tetramisole. The doses required to attain -88 percent efficacy also indicate approximately eightfold superiority of the m-amino compound.

TABLE 2 Data on the acute oral toxicity to mice of various single oral doses of the above compounds and several analogs were obtained by conventional procedures, (Table 3 hereinafter). These m-amino and substituted m-amino analogs of tetramisole are considerably more toxic than tetramisole in agreement with their higher anthelmintic activity. However, all compounds including tetramisole have a similar chemotherapeutic index, i.e., LD /ED of tento twentyfold. All compounds were well tolerated at dosages required for complete worm removal.

TABLE 3 Mouse Oral Toxicity oi Various Tetramisoles, Mg./Kg.

Phenyl substltuent None m-NHz m-NHz I m-NHHCO m-NH-CH; m-NH-COH '2 Stereo isomer d1 d1 1 d1 d1 d1 Dose, mg./kg.: Dead/total Approx. 176 15 30 Approx. I 1 76 3 Approx 1') 15 10 All other compounds 2,3,5,tl-tctrah vdroimidazothinzoles. W w, w... t r. o

EXAMPLE l9 EXAMPLE 20 Using procedures of Example 16, the approximate single dose oral ED values against N. dubius in mice were determined for tetramisole and analogs with various substituents on its phenyl ring (Table 4 hereinafter). The unexpected high activity of dl-m-amino tetramisole is attributable to its laevo component; and not only amino, but also various substituted Dogs infected with mature adult whipworms Trichuris vulpis were treated with various single or double doses of unsubstituted or substituted tetramisole analogs by the oral or subcutaneous route (Table 5 hereinafter). whipworms passed in the feces were collected for several days, and the whipworms still present determined at necropsy. Percent efficacy was amino groups in the meta position increased activity over determined in these critical" tests. The meta-amino analogs tetramisole. identical substituents in the para or ortho posihad surprisinglgchigher activity than unsubstituted tetramisole tions were less active than tetramisole; as were other types of E Pmneous doses whlch were nontoxlc for the substituents in the meta position. Particularly noteworthy was QE Tnchurfs a type Pfflematode refacmry to treatment higher quantitative activity than for the meta-nitro analogs. most P anthelnumlcs at well tolerated dosesonomically allied nematodes, e.g., Trichinella and Capillaria TABLE 4 are also refractory to most anthelmintics.

Comparative Oral Eflicacy of Various Tetramisoles Against N. dubius gg 'f We claim:

a Stereo Substituent/ l. A dl or 1 compound selected from the group consistin of isomer Salt on phenyl Meta Para Ortho those fth f l N S I N S 1 NH; N i NH; N

and pharmaceutically acceptable acid addition salts thereof.

2. A compound in accordance with claim 1, dl or l-6-(maminophenyl )-2,3 ,5 ,6-tetrahydroimidazo[ 2, l -b]thiazole.

3. The compound in accordance with claim 1, l-6-(maminophenyl )-2,3 ,5 ,6-tetrahydroimidazo[ 2, i b thiazole.

4. A compound in accordance with claim 1, wherein the salt This compound, 5,6-dihydro imidazothiazolc-all others 2,3,5,6-

tctrahyrlro. is a hydrochloride salt.

N o'rE. Indicates inactive at dose shown. I 7 W i a t 3* TABLE 5 Comparative Oral or Subcutaneous (SC) Activity vs. Mature Trichuris vulpis in Dogs Maximum non-lethal dose for Percent eflicaey orally at Meta dog, mg./kg. mgJkg. of- Percent etficaey SC at mgJkg. Stereo substituent isomer on phenyl Oral SC 5 2. 5 1. 25 20 15 10 5 2. 5 1. 25

d] H 20 25 2 l H (2) 43 (2) 50 (2) dl NH: 7.5 00 (3) 92 (2) i NH2 10 4 100 100 (2) 100 (2) 72 (4) dl ,NH-HCO 7.5 5 100 83 1 NH-HCO 2.5 100 (2) 'dl NIT-CH 10 30 100 1 10 mg./kg.).

Other values in equal number of dogs when more than one. Percent eflicacy based on total worms removed and present in all dogs at each dose shown.

b Average dose 1.5 (1.25-1.75).

1 Total dose given twice a day.

Y Two dogs single dose, other total twice a day dose.

N0'rE. Means inactive at dose shown.

' UNITED STATES PATENT OFFIQE CERTIFICATEOF CORRECTION Patent NQ. 23, 73,205 Dated June 27, "1972 Invento r(s). Lejrr ine n p e? and JohnfJames Hand I It is certified that-error appears-in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 10, Claim 1, please delete both formulas and insert the following formula as follows:

Signed and sealed this 2nd day of January 1973.

(SEAL) Attest:

' EDWARD M.PLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents FORM PO-1050 (10-69) 1 I scgymppc 50375- 559 i 0.5. GOVIINIIINT PRINTING omcl m9 0-in-3 

2. A compound in accordance with claim 1, dl or l-6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 3. The compound in accordance with claim 1, l-6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 4. A compound in accordance with claim 1, wherein the salt is a hydrochloride salt. 